title: Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling.
abstract: A detailed understanding of the mechanisms by which tumors acquire resistance to targeted anticancer agents should speed the development of treatment strategies with lasting clinical efficacy. RAF inhibition in BRAF-mutant melanoma exemplifies the promise and challenge of many targeted drugs; although response rates are high, resistance invariably develops. Here, we articulate overarching principles of resistance to kinase inhibitors, as well as a translational approach to characterize resistance in the clinical setting through tumor mutation profiling. As a proof of principle, we performed targeted, massively parallel sequencing of 138 cancer genes in a tumor obtained from a patient with melanoma who developed resistance to PLX4032 after an initial dramatic response. The resulting profile identified an activating mutation at codon 121 in the downstream kinase MEK1 that was absent in the corresponding pretreatment tumor. The MEK1(C121S) mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Thus, MEK1(C121S) or functionally similar mutations are predicted to confer resistance to combined MEK/RAF inhibition. These results provide an instructive framework for assessing mechanisms of acquired resistance to kinase inhibition and illustrate the use of emerging technologies in a manner that may accelerate personalized cancer medicine.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, D1542, Boston, MA, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Caroline
authors.initials: C
authors.lastname: Emery
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Allison
authors.initials: A
authors.lastname: Sawyer
authors.forename: Panisa
authors.initials: P
authors.lastname: Pochanard
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Kehoe
authors.forename: Cory M
authors.initials: CM
authors.lastname: Johannessen
authors.forename: Laura E
authors.initials: LE
authors.lastname: Macconaill
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D017809:Fatal Outcome; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D009154:Mutation; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics; D057285:Precision Medicine / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human